WO2009067473A2 - Method of improving palliative care - Google Patents

Abstract

The present invention provides methods and compositions for genomic screening in hospice and palliative care that will be useful to a patient's caregivers (such as advanced practice nurses, health care institutions, pharmaceutical, cultural and biotech companies will also find utility) in making treatment decisions.

Description

METHOD OF IMPROVING PALLIATIVE CARE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 60/989,328 filed November 20, 2007, the entirety of which is hereby incorporated by reference herein for all purposes.

STATEMENT OF FEDERALLY SPONSORED RESEARCH

[0002] Not Applicable.

FIELD OF THE INVENTION

[0003] The invention relates generally to the methods of improving palliative care.

BACKGROUND OF THE INVENTION

[0004] Until the recent past, cancer pain patients have been denied access to specialists and technologies directed to their unique needs, possibly under the assumption that scarce resources in both care and research are more appropriately deployed elsewhere in the years of life. Decades of sustained advocacy by both physicians and non-medical stakeholders alike were required before recognition of the possibility for significant improvements gave rise in the 1990s to new disciplines and institutions, including palliative care and hospice. Nevertheless, it remains the case that patients in the terminal stages of disease progression are rarely participants in, or beneficiaries of, new and emerging advances in biotechnology that target symptom management.

[0005] Nor have contemporary methods of symptom control closed the gap between the best of conventional care and pathways that might be envisioned. For example, Grossman et al. note: "Unfortunately, despite the scientific, therapeutic, and health-care advances of the past 20 years, barriers to providing adequate pain management to patients with cancer persist, and current estimates suggest that as many as 50% of patients are inadequately treated" (Grossman, et al. Oncology 20: 1333-1339; 2006).

[0006] In an accompanying editorial, Von Gunten and Loscalzo add: "hi advanced stages, that increases to 80%. hi the United States, there are about 2.5 million people living with cancer, and about 500,000 die of cancer each year. This means there are about 1.25 million people with cancer and moderate to severe pain; 750,000 of those have inadequate control. Of the 400,000 with advanced cancer and severe pain, 200,000 a year have inadequate control" (Von Guten, 2006).

[0007] Reliance on "one-size-fits-all" drug selection and dosing as a starting point, to be corrected by "trial-and-error" as breakthrough pain or complications arise, is a major contributor to inadequate cancer pain management in contemporary practice. Potent drugs for pain and sedation may be prescribed to the thresholds of toxicity and beyond, and attempts to control the side effects of one drug maybe met with the addition of another. Moreover, symptoms dictating intervention are frequently heterogeneous and present in patient-specific combinations, including pain of distinct origins (e.g., visceral, neuropathic, and somatic pain), nausea and other gastrointestinal disorders, over-sedation, dyspnea, insomnia and disorders of mood. Multiple drugs with widely divergent modes of action, but with overlapping pathways of absorption, distribution, metabolism and excretion, may be required in single patients, including, for example, oral and parenteral opioids, COX-2 inhibitors, tricyclic antidepressants, anticonvulsants, benzodiazepines, propofol, local anesthetics and alpha-2 agonists, hi particular, medications used in the care of patients with cancer pain are often characterized by a narrow therapeutic ratio, wide inter-individual variability, and are delivered in settings of polypharmacy and co-existing disease.

[0008] While the origins of drug toxicity, and lack or loss of efficacy, are increasingly tied to genetic predispositions in multiple medical settings, pharmacogenomic profiling has never before been directed to symptom management in cancer care extending from diagnosis to either cure or the end of life (Phillips, et al. JAMA 286: 2270-2279; 2001, Lotsch J, et al. Pain 121 : 1-5; 2006).

SUMMARY OF THE INVENTION

[0009] Here, the inventors demonstrate methods and compositions for genomic screening in hospice and palliative care that will be useful to a patient's caregivers (such as advanced practice nurses, health care institutions, pharmaceutical, cultural and biotech companies will also find utility) in making treatment decisions. [00010] In a first embodiment, the invention comprises a method of screening a palliative care or hospice care patient to determine treatment options for conditions associated with genetic variations comprising obtaining a sample such as a blood sample from the patient; and subjecting the sample to an assay for detecting two or more nucleic acid genetic markers in two or more genes associated with two or more conditions to generate a genomic profile for use in selecting a palliative care course of action such as administering a drug, a surgical or medical procedure. The genomic profile comprises information pertaining to pharmacodynamic efficacy and adversity, pharmacokinetic efficacy and adversity, a presymptomatic diagnosis and to differential diagnosis of one or more symptoms. The two or more nucleic acid genetic markers preferably comprise polymorphisms in two or more genes selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1 , NMDA, NKl and 5HT3. Alternatively, the two or more nucleic acid genetic markers comprise polymorphisms in two or more genes, selected from the group comprising ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, ILlS, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender. The two or more nucleic acid genetic markers may comprise two, five, ten or more polymorphisms in two, five, ten or more genes

[00011] In a second embodiment, the invention provides a method of screening a palliative care patient to determine drug and procedural efficacy and adversity associated with known genetic variations comprising obtaining a sample from a palliative care subject and subjecting the sample to an assay for detecting two or more nucleic acid genetic markers in two or more genes associated with two or more conditions selected from the group comprising somatic pain, visceral pain, neuropathic pain, nausea, over-sedation, dyspnea, cachexia, insomnia, fatigue and disorders of mood to generate a genomic profile, wherein the genomic profile provides information for use by a physician in determining a course of action during palliative care.

[00012] In a third embodiment, the invention provides a method comprising providing a sample obtained from a palliative care subject; and an assay for detecting two or more genetic markers, wherein the markers comprise polymorphisms in two or more genes selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1 , NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, IL18, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl₁ FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender; and subjecting the sample to the assay to generate a genomic profile for use in selecting conditions for a palliative care course of action.

[00013] In a fourth embodiment, the invention provides a kit for generating a palliative care genomic profile for a subject, comprising reagents configured such that when exposed to a sample containing target nucleic acid from a palliative care subject the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, FJ, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NK, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IU, IL6, IL8, ILlO, ILl 2, ILl 3, ILl 8, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27mά loci specific for female and male gender so as to generate a genomic profile for use in selecting a palliative care course of action for the subject; and a computer program on a computer readable medium comprising instructions which direct a processor to analyze data derived from use of the reagents. The instructions translate the data into information of predictive value for a clinician, a risk assessment for treatment options and generate a report for display either as a printed report or on a computer screen to a clinician.

[00014] The instructions also receive, process and transmit the data to and from the subject, a clinical laboratory and medical personnel using an electronic communication system, hi one version, the electronic communication system transmits the data to a distant computer system for processing, hi short, the instructions direct the fate of the data according to the subject's preference. The instructions also comprise information to optimize palliative care that, based on at least the presence of variant alleles of two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl₁ CYP2D6, CYP3A4, CYP 1A2, F2, F5,βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, ILl 8, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB 27 and loci specific for female and male gender directs a user to a specific palliative care clinical pathway for the subject.

[00015] In a fifth embodiment, the invention provides a kit for generating a palliative care genomic profile for a subject, comprising reagents configured such that when exposed to a sample containing target nucleic acid from a palliative care subject the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IU, IL6, IL8, ILlO, IL12, IL13, IL18, IL-IRa₁ PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB 27 and loci specific for female and male gender so as to generate a genomic profile for use in selecting a palliative care course of action for the subject; and a computer program on a computer readable medium comprising instructions which direct a processor to analyze data derived from use of the reagents to indicate a palliative care treatment course of action.

[00016] In a sixth embodiment, the invention provides a palliative care genomic profile kit having component parts configured such that when exposed to a sample containing target nucleic acid from a palliative care subject the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYPl A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, IL18, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender so as to generate a genomic profile for use in selecting a palliative care course of action for the subject and thereby providing a subject-specific clinical pathway for the subject comprising information to optimize palliative care that, based at least on the presence or absence of the variant alleles of two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYPl A2, F2, F5, barrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, ILl 8, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender measured by the kit, directs a user to a specific pathway of clinical intervention for the subject.

[00017] In a seventh embodiment, the invention provides a kit for generating a palliative care genomic profile for a subject, comprising reagents configured such that when exposed to a sample containing target nucleic acid from a palliative care subject the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes associated with two or more conditions selected from the group comprising somatic pain, visceral pain, neuropathic pain, nausea, over- sedation, dyspnea, cachexia, insomnia, fatigue and disorders of mood so as to generate a genomic profile for use in selecting a palliative care course of action for the subject; and a computer program on a computer readable medium comprising instructions which direct a processor to analyze data derived from use of the reagents.

[00018] Other objects, features and advantages of the present invention will become apparent after review of the specification, claims and drawings.

DESCRIPTION OF THE INVENTION I. In General

[00019] Before the present materials and methods are described, it is understood that this invention is not limited to the particular methodology, protocols, materials, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by any later-filed nonprovisional applications.

[00020] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. As well, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein. It is also to be noted that the terms "comprising", "including", and "having" can be used interchangeably. [00021] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications and patents specifically mentioned herein are incorporated by reference for all purposes including describing and disclosing the chemicals, instruments, statistical analysis and methodologies which are reported in the publications which might be used in connection with the invention. All references cited in this specification are to be taken as indicative of the level of skill in the art, and are incorporated by reference in their entirety for all purposes. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

IL The Invention

[00022] The present invention provides methods and compositions for genomic screening in hospice and palliative care that will be useful to a patient's caregivers (such as advanced practice nurses, health care institutions, pharmaceutical, cultural and biotech companies will also find utility) in making treatment decisions. Ln some embodiments, the genomic screening is designed to test for mutations and polymorphisms related to a subject's risk for drug-related complications. For example, one may wish to screen for pharmacokinetic complications (e.g., arising from abnormal drug absorption, distribution, metabolism, and excretion), and pharmacodynamic complications (e.g., inefficacy and/or toxicity). Ln other embodiments, the palliative genomic screen is designed to test for specific mutations or polymorphisms relevant to other types of complications during palliative care, for example, disorders of mood, metabolism, pulmonary or circulatory dysfunction, or thrombosis. One skilled in the relevant art understands that the present invention encompasses palliative care genomic profiles for additional disorders other than those listed above.

[00023] As disclosed below, markers for inclusion in palliative care genomic profiles are selected based on specific criteria. For example, the sequence of the mutation or polymorphism, as well as the clinical outcome of carrying a mutant allele, should be known. In preferred embodiments, markers are selected for which there is no current alternative diagnostic test or the available test is not suited for palliative care screening. LQ particularly preferred embodiments, markers are selected for which a clinical course of treatment can be altered in response to the presence or absence of a mutation or polymorphism.

A. Selection of Markers for Genomic Profile

[00024] To generate the palliative care genetic profiles of the present invention, markers are first selected for inclusion in the profile. Preferably, the sequence of the markers is known. In preferred embodiments, the markers are mutations in a given gene known to have an associated phenotype. Large amounts of sequence data and known mutations or polymorphisms are known and accessible. In preferred embodiments, markers are selected for their utility in providing information relevant to palliative care and hospice care.

[00025] Preferred markers for one embodiment of the present invention compromise at least two, five or ten markers selected from genes in the group including OPRM-I, OPRDl, CYP2D6, CYP3A4, CYPl A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1 , NMDA, NKl and 5HT3. However, the present invention is meant to encompass known markers and markers yet to be characterized, including without limitation the markers in Table 1 as well as loci specific for female and male gender.

[00026] Table 1 : Additional Loci at which polymorphisms have been identified that fulfill the categories and selection criteria disclosed herein.

[00027] The sections below describe methods of obtaining and evaluating suitable markers that would be useful to one of skill in the art of palliative patient care. B. Sequence Data

[00028] In some embodiments of the present invention, the genetic markers are single nucleotide polymorphisms ("SNPs"). Known SNPs are available from public and private databases, hi other embodiments, the markers are mutations {e.g., nucleotide deletions or insertions). In some embodiments, the markers represent splice variations. In further embodiments, the markers represent variable number sequence repetitions. In other embodiments, the markers are epigenomic markers, for example, methylation markers, or histone acetylation markers. In some embodiments, the markers direct selection of alternative tRNAs in protein translation. In other embodiments, the markers represent mutations in mitochondrial DNA.

[00029] hi addition to known SNPs, a variety of nucleotide sequence information describing wild type and mutant alleles of a large number of genes is available in public databases including, but not limited to DbEST (http://www.ncbi.nlm.nih.gov/dbES); EBI/EMBL

(http://www.ebi.ac.uk/mutations); EBI (http://www.ebi.ac.uk/ebi_home.html); EMBL (http://www.ebi.ac.uk/queries/queries.html); GDB (http://www.gdb.org/gdb/gdbtop.html); GeneCards (httpV/bioinformatics.weizmann.ac.il/cards/index.html); GeneClinics

(http://www.geneclinics.org); Genethon (http://www.genethon.fr/genethon_en.htrnl); GSDB (http://www.ncgr.org); HGP (http://www.ornl.gov/TechResources/Human_Genome/home.html); Human Gene Mutation Databoase (http://www.uwcm.ac.uk/uwcm/mg/search); NCBI (http://www.ncbi.nlm.nih.gov/); OMIM (http://www.ncbi.nlm.nih.gov/Omim/); PubMed (http://www.ncbi.nlm.nih.gov/PubMed/); Research Tools (NCBI)

(http^/www.ncbi.nlm.nih.gov/SCIENCEPό/ResTools.htm^j RHdb (http://www.ebi.ac.uk/RHdb); Stanford Human Genome Center (http://www.shgc.stanford.edu/); HUGO (http://www.gene.ucl.ac.uk/hugo); TIGR (http://www.tigr.org/); The National Human Genome Research Institute (http://www.nhgri.nih.gov/); The Whitehead Institute Center for Genome (http://www.genome.wi.mit.edu/); Unigene (http://www.ncbi.nlm.nih.gov/Unigene/index.html); University of Oklahoma (http://www.dnal.chem.ou.edu/index.html); and WEHI (http : //wehih. wehi . edu.au/srs/srsc/) . [00030] One skilled in the art of palliative patient care understands that nucleotide sequence data may be also be obtained from additional sources, including, but not limited to public and private databases, and is obtainable experimentally.

C. Criteria for Selection of Markers

[00031] In preferred embodiments of the present invention, the genetic markers selected for palliative care genomic profile are tailored towards a specific drug, disorder or subset of patients. The markers are selected based on several criteria, including but not limited to analytical validity, clinical validity, clinical utility, and commercial value.

[00032] In some embodiments of the present invention, markers are selected for their analytical validity (e.g. , accuracy of detection using a particular detection technique). Markers are also selected based on their clinical validity, or their predictive effect (e.g., the marker accurately predicts a subject's response to a specific aspect of the treatment). The sequence of all the mutations or polymorphisms to be tested should be available. For markers with multiple SNPs or mutations, it is preferred that the phenotypic outcome of each nucleotide change is known. It is also preferred that markers are selected for which the predisposition is unable to be determined (e.g., cannot be determined cheaply or efficiently) through alternative means of detection, such as medical history, physical exam, or a non-genomic assay.

[00033] hi some embodiments of the present invention, markers are selected in which the alternative treatment has little or no effect on the cost or inconvenience to the subject. Thus, markers are selected for which neither a false negative result (the original drug is prescribed and the patient is in no worse a situation than if the assay had not been done) nor a false positive result (the alternative treatment is of equivalent cost and risk to original treatment) has a detrimental effect on subject outcome.

[00034] hi some embodiments, the palliative care genomic profile includes two or more markers. Ln other embodiments, the palliative genomic profile includes five or more markers. In some embodiments, the palliative genomic profile includes 10 or more markers, hi some preferred embodiments, the palliative care genomic profile includes 20 or more markers. La other preferred embodiments, the palliative care genomic profile includes 50 or more markers. In some particularly preferred embodiments, the palliative care genomic profile includes 100 or more markers. However, the utility of the assay is determined primarily by the predictive outcome of the individual markers or combination of markers, not the quantity of markers included.

[00035] In particularly preferred embodiments, markers are selected that provide information that can be used to alter the course of treatment (i.e., the markers have clinical utility). For example, if a subject is found to be predisposed to react poorly to one of several drugs commonly given during palliative care or hospice care, the practitioner may choose an alternative drug, dose, route or regimen. Of particular utility are markers for predispositions for which an alternative treatment, equivalent in cost or ease of administration, can be substituted, thus reducing suffering and decreasing the number of expensive life-threatening complications (i.e., the inclusion of a given marker has the added advantage of having commercial value). In addition, markers are selected for which a negative result (e.g. , the absence of an underlying condition) has clinical utility (e.g. , aids in the differential diagnosis of a disease).

[00036] hi some embodiments, the addition or subtraction of markers from the genomic profile is determined experimentally. For example, if it is determined that a marker does not correlate well with a subject's response to a given component of the treatment, the marker is subtracted. The inclusion of new markers may also be determined empirically. For example, if a new marker is found to have good predictive ability, alone or in combination with other markers, that marker is added to the palliative care genomic profile.

D. Categories of Markers

[00037] In some preferred embodiments, markers that measure a subject's pharmacogenetic risk (response to pharmacological compound) are included. In some embodiments, markers for a subject's pharmacodynamic risk (a response of abnormal magnitude triggered by a pharmacological agent; e.g. , serotonin syndrome, or bronchospasm unrelieved by an abnormal β2 adrenergic receptor response to a β2 agonist) are included in the palliative care genomic profile, hi still further preferred embodiments, markers that predict a subject's pharmacokinetic response (abnormal adsorption, distribution, metabolism and excretion of a drug, resulting in overdose or lack of efficacy of a drug; e.g. , cytochrome P450 mutations that effect the metabolism of a variety of drugs) are included in the palliative care genomic profile.

[00038] In some preferred embodiments, markers with diagnostic utility are included in the palliative care genomic profile. In further preferred embodiments, markers that identify preexisting but non-symptomatic conditions that are relevant to palliative care or hospice care (e.g., long QT syndrome that may manifest in response to particular drugs) are included in the palliative care genomic profile.

[00039] In additional preferred embodiments, markers are included that establish the differential diagnosis of symptomatic disorders that may resemble one another outwardly, but require different interventions during palliative care and hospice care.

[00040] hi some embodiments, the palliative care screening assay includes markers tailored to the specific drugs or disorders, hi some embodiments, the palliative care genomic profile includes markers unique to a subject in a certain group (e.g., age, ethnic background, gender).

[00041] In some embodiments, markers included in the genomic profile are haplotypes, or the natural variation within a gene unique to a given group of subjects (e.g. , a family of blood-relatives). Some haplotypes predict the response to a given pharmaceutical agent (e.g., lack of response to a given drug).

[00042] Ln some embodiments, additional markers are included that predict common complications during palliative care and hospice care. Examples include, but are not limited to markers for cacheixa/malnutrition, blood groups, coagulation factors, and thrombosis risk. In some embodiments, the palliative care genomic profile includes a unique genomic identifier (e.g. , a series of polymorphic non-coding SNPs), thus providing a secure, accurate internal reference for archiving and tracking genetic data specific to the particular subject.

[00043] In another embodiment, markers are selected from variant alleles in two or more genes associated with two or more conditions closely associated with palliative care. Preferably, the markers are selected from the group of conditions consisting of somatic pain, visceral pain, neuropathic pain, nausea, over-sedation, dyspnea, cachexia, insomnia, fatigue and disorders of mood. [00044] In another embodiment of the present invention, markers that are indicative of genetic information that does not obey Mendelian rules are suitable. For example, genetic elements that are passed onto an offspring through transposition, gene conversion, unequal chromosomal crossover and/or segregation distorter are examples of non-Mendelian inheritance. In other examples, the genetic elements may be inherited from one parent, for example through mitochondrial inheritance. The present invention is also suitable for markers that indicate an epigenetic inheritance, a term used to refer to features (e.g. chromatin and DNA modifications) that may be stable over rounds of cell division and involve a role in the process of cellular differentiation. These features may allow cells to maintain different characteristics despite containing the same genomic material. Some epigenetic features are known to show transgenerational inheritance. The present invention merely requires that one obtain suitable markers useful for one of skill in the art in palliative patient care to determine a course of palliative treatment.

E. Palliative Care

[00045] As defined in the present application, a patient is a "palliative care patient" if the patient is receiving medical or comfort care that reduces the severity of a disease or slows its progress rather than providing a cure in the judgment of one of skill in the art of palliative patient care. For incurable diseases, in cases where the cure is not recommended due to other health concerns, and when the patient does not wish to pursue a cure, palliative care becomes the focus of treatment. For example, if surgery cannot be performed to remove a tumor, radiation treatment might be tried to reduce its rate of growth, and pain management could help the patient manage physical symptoms.

[00046] The National Hospice and Palliative Care Organization (NHPCO's) Standards of Practice or Hospice Programs describes palliative care as treatment that enhances comfort and improves the quality of an individual's life during the last phase of life. No specific therapy is excluded from consideration. The test of palliative care lies in the agreement between the individual, physician(s), primary caregiver, and the hospice team that the expected outcome is relief from distressing symptoms, the easing of pain, and/or enhancing the quality of life. The decision to intervene with active palliative care is based on an ability to meet stated goals rather than affect the underlying disease. [00047] As used herein, "palliative care" means the care of the dying, end of life care, care aimed at improving the quality of life of a patient with the symptoms of one or more diseases. The central objective of palliative care is relief and the prevention of suffering and improvement of the quality of life through symptom control at the end of life. Palliative care is not aimed at a cure of the one or more diseases. Palliative care begins when curative treatment is no longer feasible. The task of palliative care is the assessment and control of symptoms, with the goal to relieve suffering. Palliative care specifically aims at the relief of symptoms at the end-stage of life. Medical conditions of people requiring palliative care include, for example, cancer, HIV/ AIDS, motor neuron disease, muscular dystrophy, multiple sclerosis, end-stage dementia, brain injuries and cerebral strokes, heart conditions, liver failure, renal failure, lung failure, Alzheimer's disease, and spinal cord injuries.

[00048] As used herein, "to palliate" means to mitigate, to alleviate, to lessen the severity of one or more symptoms or to give temporary relief of one or more symptom. See, for example, Pastrana T, Junger S. A matter of definition - key elements identified in a discourse analysis of definitions of palliative care {Palliative Medicine 2008; 22: 222-232).

[00049] In a preferred version of the present invention, the term "palliative care" describes care to patients who agree to therapy with a palliative intent, have a life expectancy of less than 6 months if the disease runs its usual course in the judgment of the patient's attending physician or a palliative care specialist. Preferably, these patients have elected the Medicare Hospice Benefit for coverage of all services related to their terminal illness (Portenoy RK. "Defining Palliative Care" The Pain Medicine and Palliative Care Newsletter, Beth Israel Medical Center Department of Pain Medicine and Palliative Care, 1 (2), 1998).

[00050] hi a particularly preferred version of the present invention, the patient has been admitted to a hospice or is undergoing "hospice care". Hospice care, which can be given in a patient's home, a hospital, nursing home or private hospice facility, is most typically defined as palliative care appropriate when the patient can no longer benefit from curative treatment and has a life expectancy of less than six months as determined by the patient's attending physician and/or a hospice medical director. F. Methods of the Present Invention

[00051] In one embodiment, the present invention is a method of screening a palliative care or hospice care patient to determine drug or procedural efficacy or adversity associated with genetic variations. This method will provide useful results to a patient's attending physician or hospice director who will be assisting the patient to make treatment decisions.

[00052] hi general, the method comprises obtaining a biological sample, preferably a blood sample, from the patient and subjecting the sample to an assay for detecting two or more nucleic acid genetic markers in two or more genes associated with two or more conditions to generate a genomic profile for use in selecting a palliative care course of action, such as administration of a drug or decisions pertaining to surgical or medical procedures. Preferred assays are described in more detail in the Examples.

[00053] hi preferred embodiments, the genomic profile will provide information pertaining to pharmacodynamic efficacy and adversity or to pharmacokinetic efficacy and adversity.

[00054] hi other preferred embodiments, the genomic profile comprises a presymptomatic diagnosis or information pertaining to differential diagnosis of one or more symptoms. Information provided in these embodiments will be important for an attending physician to provide the most effective pharmaceutical and treatment interventions for the palliative care patient.

[00055] hi another embodiment, the present invention comprises a method of screening a palliative or hospice care patient to determine drug and procedural efficacy and adversity associated with known genetic variations. The method comprises obtaining a sample, preferably a blood sample, from the patient and subjecting the sample to an assay for detecting at least two, at least five or at least ten nucleic acid genetic markers in two or more genes associated with two or more conditions selected from the group comprising somatic pain, visceral pain, neuropathic pain, nausea, over-sedation, dyspnea, cachexia, insomnia, fatigue and disorders of mood to generate a genomic profile. These conditions are particularly important in palliative care patients and the genomic profile will provide information for use by a physician in determining a course of action during palliative care. In one embodiment, the genomic profile comprises information pertaining to differential diagnosis of one or more of these conditions.

[00056] Following selection of markers for inclusion in a given genomic profile, one would then perform an assay for detection of the markers. In some embodiments, the assay is a direct sequencing assay. In other embodiments, the assay is a fragment length polymorphism assay. In some preferred embodiments, the assay is a hybridization assay. In some preferred embodiments, the assay is a hybridization assay incorporating detection by enzymatic means. In other preferred embodiments, the assay is a MALDI-TOF mass spectrophotometric assay, hi particularly preferred embodiments, the assay is a pyrosequencing assay. The genomic profiles of the present invention find use with any detection method capable of detecting specific sequences and may be applied to detection methods developed in the future which may, or may not, rely on nucleic acid hybridization, hi some embodiments, the process of selecting markers, performing detection assays, and distributing data to subjects and clinicians is organized by an integrated electronic (e.g., web-based) system.

G. Kits of the Present Invention

[00057] In another embodiment, the present invention is a kit for generating a palliative care genomic profile for a subject. Preferably, the kit comprises reagents configured such that when the reagents are exposed to a sample containing target nucleic acid from a palliative care subject, the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes selected from the group of genes comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP 1A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, IL18, IL-IRa, , PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender so as to generate a genomic profile for use in selecting a palliative care course of action for the subject. Preferably, the kit comprises a computer program on a computer readable medium comprising instructions which direct a processor to analyze data derived from use of the reagents. [00058] In a preferred embodiment of the present invention, the instructions translate the data into a risk assessment for treatment options or recommendations for treatment options.

[00059] In another embodiment, the instructions generate a report for display to a clinician and/or is in the form of a report that can be printed and or the display is in the form of a report on a computer monitor. Additionally, the instructions are preferably sufficient to receive, process and transmit the data to and from the subject, a clinical laboratory and medical personnel and the electronic communication system transmits the data to a distant computer system for processing and/or the instructions direct the fate of the data to the subject's preference.

[00060] hi another embodiment, the kit instructions that comprise information to optimize palliative care that, based on the presence of variant alleles associated with two or more, five or more, or ten or more genes selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYPl A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, IL18, IL- IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender directs a user to a specific palliative care clinical pathway for the patients.

[00061] In another embodiment, the present invention is a palliative care genomic profile kit having component parts configured such that when exposed to a sample containing target nucleic acid from a palliative care patient are sufficient to detect the presence or absence of variant alleles in two or more, five or more or ten or more genes selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, ILl 8, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender so as to generate a genomic profile for use in selecting a palliative care course of action for the patient and provide a subject-specific clinical pathway for the patient comprising information to optimize palliative care that, based at least on the presence or absence of the variant alleles of two or more, five or more, or ten or more genes selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5, barrestin2, stat2, COMT, MTHFR, A2a, melanocortin-l,NMDA, NKl and 5HT3 that were measured by the kit, directs a user to a specific pathway of clinical intervention for the patient. Sample components would include primers designed to identify markers of the present invention, buffers, marker dyes, electropheretic gels and sample vessels. The kit is configured to test a sample for polymorphisms in all of the recited genes and others that could be added or envisioned.

[00062] In another embodiment, the present invention is a kit for generating a palliative care genomic profile for a subject, comprising reagents configured such that when exposed to a sample containing target nucleic acid from a palliative care subject the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes associated with two or more conditions selected from the group comprising somatic pain, visceral pain, neuropathic pain, nausea, over- sedation, dyspnea, cachexia, insomnia, fatigue and disorders of mood so as to generate a genomic profile for use in selecting a palliative care course of action for the subject; and a computer program on a computer readable medium comprising instructions which direct a processor to analyze data derived from use of the reagents.

III. EXAMPLES

[00063] Preliminary Data, hi an investigation related to the present application, 10 patients were tested for 16 polymorphisms in genes predicting phenotypes of interest to palliative care providers i.e. , beta arrestin 2 (ARRB2 T822C), multiple drug resistance gene 1 (ABCBl T3435C), cytochrome P450 (CYP2C9*2, CYP2D6H, CYP3A5*6), factor V Leiden (FVL), prothrombin II (F2), hydroxytryptamine 2 A (5-HT(2A) T 102C), interleukin 1 beta (IL-IB T-31C, C-511T), mu-opioid receptor (OPRMAl 18G), methylene tetrahydrofolate reductase (MTHFR C677T), cyclooxygenase-2 (PTGS2 G-765C), stat 6 (STAT6 C-1714T, T9056C), and TGF beta (TGFB rs224172). All alleles were tested by PCR followed by restriction fragment length digestion and gel electrophoresis (Fig. 1 ), and by pyrosequencing (King, 2006) (Fig. 2) or di-deoxy sequencing, hi this sample, no patient was wild type at all loci, and homozygous mutants were observed in at least 1 of 10 patients in 9 of the 16 loci tested (Fig. 3). These results demonstrate that pyrosequencing, exhibits a high degree of analytical validity when compared to PCR followed by RFLP, with only a single discordant result observed in ARRB2 T822C between the two methods. [00064] Evaluation Methodolgy and Data Analysis. The number of homozygous and aggregate (homozygous plus heterozygous) mutant alleles is scored for each patient. The aggregate mutant allele score in the cancer pain pharmacogenomic profiles is meaningful because the contribution of multiple heterozygous alleles in a shared pathway may be equivalent to, or even exceed, the impact of a single homozygous mutant genotype to the symptom of interest. As well, the observed allele frequencies for each locus is compared with those reported in publications describing relevant populations, and with the results of earlier investigations with alleles that may be shared between panels assembled for distinct purposes, e.g. perioperative genomic profiles vs. pharmacogenomic profiles in cancer pain.

[00065] The recorded phenotypic data is used to identify and quantify details of drug selection, dosing and regimens in contemporary local practice, together with acquisition of objective evidence indicating drug efficacy i.e., how well the chosen analgesics and adjuvants are working for their desired effects. In turn, the incidence of phenotypes indicating toxicity (e.g. , adverse drug responses, drug interactions) is ascertained as a predicate to drawing genotype - phenotype correlations in the target cancer pain population.

[00066] A Y² goodness of fit test (Snedecor, 1989) is used to determine whether allele frequencies are distributed accordance with the principles of the Hardy Weinberg equilibrium (Cannings, 1969). To test the influence of a single genotype, or collection of genotypes, on clinical outcomes in cancer pain, Fisher's exact test is used for analysis of qualitative outcomes, an unpaired Student's t-test corrected for unequal variance or the Mann- Whitney U test is used for analysis between continuous outcomes, and a one way ANOVA is used for comparisons across multiple groups. The methods are repeatedly applied for each genomic marker, and a Bonferonni correction is performed to account for multiple testing. To test for information present in dependence among markers, a standard regression analysis is used to correct for covariates using empirical Bayes methods (Kendziorski, 2003). A significance level of P <0.05 will be adopted for all comparisons. References

[00067] The following references are submitted as illustrative of suitable markers and contain information that would be useful to one of skill in the art (e.g. an attending physician or hospice director) in selecting a suitable panel for best analysis of palliative care protocols, and are hereby incorporated by reference in their entirety for all purposes.

A. Select alternative doses and alternative drugs for nausea.

[00068] Babaoglu MO, Bayar B, Aynacioglu AS, et al. Association of ABCBl 3435OT polymorphism with antiemetic efficacy of 5-hydroxytryptamine type antagonists. Clin Pharmacol Ther 78: 619-626' 2005.

[00069] Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: Do CYP2D6 copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology 102: 543-549; 2005.

[00070] Grossman SA, Dunbar EM, Nesbit SA. Cancer pain management in the 21^st century. Oncology 20: 1333-1339; 2006.

[00071] Ho KY, Tong JG. Pharmacology, pharmacogenetics, and clinical efficacy of 5- hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol 19: 606-611; 2006.

[00072] Janicki PK. Cytrochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Med Sci Monit 11: 322-328; 2005.

[00073] Janicki PK, Schuler HG, Jarzembowski TM, et al. Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP2D6 genotype. Anesth Analg 102: 1127-1133; 2006.

[00074] Snedecor, GW, Cochran WG. Statistical Methods Iowa State Univ. Press, Ames., 1989.

[00075] Stromgren AS, Sjogren P, Goldschmidt D, et al. Symptom priority and course of symptomatology in specialized palliative care. Pain Symptom Manage 31: 199-206; 2006. [00076] Sugai T, Suzuki Y, Sawamura K, et al. The effect of 5-hydroxytryptamine 3 A and 3B receptor genes on nausea induced by parozetine. Pharmacogenomics 6: 3510356; 2006.

[00077] Von Gunten CF, Loscalzo MJ. Cancer pain management in the 21^st century: Discussion. Oncology 20; 1351.

B. Select alternative doses and alternative drugs for sedation

[00078] Cannings, C, Edwards WA. Expected genotypic frequencies in a small sample: deviation from Hardy- Weinberg equilibrium. Am J Hum Genet 21: 245-251; 1969.

[00079] Chang VT, Hwang SS, Feuerman M. Validation of the Edmonton symptom assessment scale. Cancer 88: 2164-2171; 2000.

[00080] Floyd MD, Gervasini G, Mascia AL, et al. Genotype-phenotype associations for common CYP3 A4 and CYP3 A5 variants in the basal and induced metabolism of midazolam in European- and African- American men and women. Pharmacogenetics 13: 595-606, 2003.

C. Select alternative doses and alternative drugs for analgesia

[00081] Hogan K, Domanico M, Caldwell M, Hogan Q, Burmester J. Perioperative genomic profiles by structure-specfic cleavage of oligonucleotide probes. American Society of Anesthesiologists, October, 2006. (available at www.anesthesiology.org)

[00082] Dceda K, Ide S, Han W, et al. How individual sensitivity to opiates can be predicted by gene analysis. Trends in Pharmacological Sciences 26: 311-317; 2005.

[00083] Jin M, Gock SB, Jannetto PJ, et al. Pharmcogenomics as molecular autopsy for forensic toxicology: Genotyping cytochrome P450 3A4*1B and 3A5*3 for 25 fentanyl cases. Journal of Analytical Toxicology 29: 590-598, 2005.

[00084] Kendziorski CM, Newton MA, Lan H, et al. On parametric empirical Bayes methods for comparing multiple groups using replicated gene expression profiles. Statistics in Medicine 22: 3899-3914; 2003. [00085] Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDRl alleles among European Americans and African Americans. Clin Pharm Ther 70: 189- 199, 2001.

[00086] King CR, Scott-Horton T. Pyrosequencing: a simple method for accurate genotyping. Methods MoI. Biol 373: 39-56; 2006

[00087] Klepstad P, Rakvag TT, Kaasa S, et al. The 118 A>G polymorphism in the human micro- opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol. Scand. 48: 1232-1239; 2004.

[00088] Lee Ys, Kim H, Wu TX, et al. Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Clin Pharm and Ther 79: 407-418; 2006.

[00089] Lotsch J, Geisslinger G. Current evidence for a genetic modulation of the response to analgesics. Pain 121 : 1-5; 2006.

[00090] Lotsch J, Geisslinger G. Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics 6: 200-210; 2006.

[00091] Phillips KA, Veenstra DL. Oren E, et al. Potential role of pharmacogenomics in reducing adverse drug reactions: a systemic review. JAMA 286: 2270-2279; 2001.

[00092] Rakvag TT, Klepstad P, Barr C, et al. The Vall58Met polymorphism of the human catechol-Omethyltransferase gene may influence morphine requirements in cancer pain patients. Pain 116: 73-78; 2005.

[00093] Ross JR, Rutter D, Welsh K, et al. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics 5: 324-336, 2005.

D. Select alternative doses and alternative drugs for depression

[00094] McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome in antidepressant treatment. Am J Hum Genet 78: 804-814; 2006. E. Select alternative doses and alternative drugs for anticoagulation and prevention of thrombosis

[00095] Moridani M, Fu L, Selby R, et al. Frequency of CYP2C9 polymorphisms affecting warfarin metabolism in a large anticoagulant clinic cohort. Clinical Biochemistry 39: 606-612; 2006.

F. Select alternative doses and alternative drugs for disorders of mood

[00096] Moro C, Brunelli C, Miccinesi G, et al. Edmonton symptom assessment scale: Italian validation in two palliative care settings. Support Care Cancer 14: 30-37; 2006.

[00097] Murphy GM, Kremer C, Rodrigues HE, et al. Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry 160: 1830-1835; 2003.

G. Reference list for Example

[00098] Babaoglu MO, Bayar B, Aynacioglu AS, et al. Association of ABCBl 3435OT polymorphism with antiemetic efficacy of 5-hydroxytryptamine type antagonists. Clin Pharmacol Ther 78: 619-626' 2005.

[00099] Candiotti KA, Birabach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: Do CYP2D6 copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology 102: 543-549; 2005.

[000100] Cannings, C, Edwards WA. Expected genotypic frequencies in a small sample: deviation from Hardy-Weinberg equilibrium. Am J Hum Genet 21: 245-251; 1969.

[000101] Chang VT, Hwang SS, Feuerman M. Validation of the Edmonton symptom assessment scale. Cancer 88: 2164-2171; 2000.

[000102] Fishbain DA, Fishbain D, Lewis J, et al. Genetic testing for enzymes of drug metabolism: Does it have clinical utility in pain medicine at the present time? A structured review. Pain Medicine 5: 81-93; 2004. [000103] Floyd MD, Gervasini G, Mascia AL, et al. Genotype-phenotype associations for common CYP3 A4 and CYP3 A5 variants in the basal and induced metabolism of midazolam in European- and African- American men and women. Pharmacogenetics 13: 595-606, 2003.

[000104] Gross SA, Dunbar EM, Nesbit SA. Cancer pain management in the 21^st century. Oncology 20: 1333-1339; 2006.

[000105] Ho KY, Tong JG. Pharmacology, pharmacogenetics, and clinical efficacy of 5- hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol 19: 606-611; 2006.

[000106] Hogan K, Domanico M, Caldwell M, Hogan Q, Burmester J. Perioperative genomic profiles by structure-specfic cleavage of oligonucleotide probes. American Society of Anesthesiologists, October, 2006. (available at www.anesthesiology.org)

[000107] Dceda K, Ide S, Han W, et al. How individual sensitivity to opiates can be predicted by gene analysis. Trends in Pharmacological Sciences 26: 311-317; 2005.

[000108] Janicki PK. Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Med Sci Monit 11 : 322-328; 2005.

[000109] Janicki PK, Schuler HG, Jarzembowski TM, et al. Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP2D6 genotype. Anesth Analg 102: 1127-1133; 2006.

[000110] Jin M, Gock SB, Jannetto PJ, et al. Pharmcogenomics as molecular autopsy for forensic toxicology: Genotyping cytochrome P450 3A4*1B and 3A5*3 for 25 fentanyl cases. Journal of Analytical Toxicology 29: 590-598, 2005.

[000111] Kendziorski CM, Newton MA, Lan H, et al. On parametric empirical Bayes methods for comparing multiple groups using replicated gene expression profiles. Statistics in Medicine 22: 3899-3914; 2003. [000112] Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDRl alleles among European Americans and African Americans. Clin Pharm Ther 70: 189-199, 2001.

[000113] King CR, Scott-Horton T. Pyrosequencing: a simple method for accurate genotyping. Methods MoI. Biol 373: 39-56; 2006

[000114] Klepstad P, Rakvag TT, Kaasa S, et al. The 118 A>G polymorphism in the human micro- opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol. Scand. 48: 1232-1239; 2004.

[000115] Lee Ys, Kim H, Wu TX, et al. Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Clin Pharm and Ther 79: 407-418; 2006.

[000116] Lotsch J, Geisslinger G. Current evidence for a genetic modulation of the response to analgesics. Pain 121 : 1-5; 2006.

[000117] Lotsch J, Geisslinger G. Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics 6: 200-210; 2006.

[000118] McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome in antidepressant treatment. Am J Hum Genet 78: 804-814; 2006.

[000119] Moridani M, Fu L, Selby R, et al. Frequency of CYP2C9 polymorphisms affecting warfarin metabolism in a large anticoagulant clinic cohort. Clinical Biochemistry 39: 606-612; 2006.

[000120] Moro C, Brunelli C, Miccinesi G, et al. Edmonton symptom assessment scale: Italian validation in two palliative care settings. Support Care Cancer 14: 30-37; 2006.

[000121] Murphy GM, Kremer C, Rodrigues HE, et al. Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry 160: 1830-1835; 2003.

[000122] Phillips KA, Veenstra DL. Oren E, et al. Potential role of pharmacogenomics in reducing adverse drug reactions: a systemic review. JAMA 286: 2270-2279; 2001. [000123] Rakvag TT, Klepstad P, Barr C, et al. The Vall58Met polymorphism of the human catechol-O-methyltransferase gene may influence morphine requirements in cancer pain patients. Pain 116: 73-78; 2005.

[000124] Ross JR, Rutter D, Welsh K, et al. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics 5: 324-336, 2005.

[000125] Snedecor, GW, Cochran WG. Statistical Methods Iowa State Univ. Press, Ames, IA, 1989.

[000126] Stromgren AS, Sjogren P, Goldschmidt D, et al. Symptom priority and course of symptomatology in specialized palliative care. Pain Symptom Manage 31 : 199-206; 2006.

[000127] Sugai T, Suzuki Y, Sawamura K, et al. The effect of 5-hydroxytryptamine 3 A and 3B receptor genes on nausea induced by parozetine. Pharmacogenomics 6: 3510356; 2006.

[000128] Von Gunten CF, Loscalzo MJ. Cancer pain management in the 21^st century: Discussion. Oncology 20; 1351.

Claims

ClaimsWe claim:

1. A method of screening a palliative care or hospice care patient to determine treatment options for conditions associated with genetic variations comprising:

a) obtaining a sample from the patient; and

b) subj ecting the sample to an assay for detecting two or more nucleic acid genetic markers in two or more genes associated with two or more conditions to generate a genomic profile for use in selecting a palliative care course of action.

2. The method of Claim 1 , wherein the course of action comprises administering a drug, a surgical procedure or a medical procedure.

3. The method of Claim 1, wherein the genomic profile comprises information pertaining to pharmacodynamic efficacy and adversity, a presymptomatic diagnosis, information pertaining to differential diagnosis of one or more symptoms or pharmacokinetic efficacy and adversity.

4. The method of Claim 1 , wherein the sample is a blood sample.

5. The method of Claim 1, wherein the two or more nucleic acid genetic markers comprise polymorphisms in two or more genes, the genes selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYPl A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl and 5HT3.

6. The method of Claim 1, wherein the two or more nucleic acid genetic markers comprise polymorphisms in two or more genes, the genes selected from the group comprising ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, IL13, IL18, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GlRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender.

7. The method of Claim 5 or 6, wherein the two or more nucleic acid genetic markers comprise five or ten or more polymorphisms in two or more genes.

8. A method of screening a palliative care patient to determine drug and procedural efficacy and adversity associated with known genetic variations comprising:

a) obtaining a sample from a palliative care subject; and

b) subj ecting the sample to an assay for detecting two or more nucleic acid genetic markers in two or more genes associated with two or more conditions selected from the group comprising somatic pain, visceral pain, neuropathic pain, nausea, over-sedation, dyspnea, cachexia, insomnia, fatigue and disorders of mood to generate a genomic profile, wherein the genomic profile provides information for use by a physician in determining a course of action during palliative care.

9. The method of Claim 8, wherein the course of action comprises administering a drug, a surgical procedure or a medical procedure.

10. The method of Claim 8, wherein the genomic profile comprises information pertaining to pharmacodynamic efficacy and adversity, a presymptomatic diagnosis, a differential diagnosis of one or more conditions or pharmacokinetic efficacy and adversity.

11. The method of Claim 8, wherein the sample is a blood sample.

12. The method of Claim 8, wherein the two or more nucleic acid genetic markers comprise polymorphisms in two or more genes, the genes selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYPl A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl and 5HT3.

13. The method of Claim 8, wherein the two or more nucleic acid genetic markers comprise polymorphisms in two or more genes, the genes selected from the group comprising ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, IL12, IL13, IL18, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB 27 and loci specific for female and male gender.

14. The method of Claim 12 orClaim 13, wherein the two or more nucleic acid genetic markers comprise five or ten or more polymorphisms in two or more genes.

15. A method comprising:

a) providing: i) a sample obtained from a palliative care subject; and ii) an assay for detecting two or more genetic markers, wherein the markers comprise polymorphisms in two or more genes selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5,βarrestin2,stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, IL12, IL13, IL18, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender; and

b) subjecting the sample to the assay to generate a genomic profile for use in selecting conditions for a palliative care course of action.

16. The method of Claim 15, wherein the course of action comprises administering a drug, a surgical procedure or a medical procedure.

17. The method of Claim 15, wherein the genomic profile comprises information pertaining to pharmacodynamic efficacy and adversity, a presymptomatic diagnosis, a differential diagnosis of one or more symptoms or pharmacokinetic efficacy and adversity.

18. The method of Claim 15 wherein the two or more nucleic acid genetic markers comprise five or ten or more polymorphisms in two or more genes.

19. A kit for generating a palliative care genomic profile for a subject, comprising:

a) reagents configured such that when exposed to a sample containing target nucleic acid from a palliative care subject the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1 , NMDA, NK, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, IL12, ILl 3, IL18, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender so as to generate a genomic profile for use in selecting a palliative care course of action for the subject; and

b) a computer program on a computer readable medium comprising instructions which direct a processor to analyze data derived from use of the reagents.

20. The kit of Claim 19, wherein the instructions direct the fate of the data according to the subject's preference, translate the data into information of predictive value for a clinician, translate the data into a risk assessment for treatment options, are sufficient to receive, process and transmit the data to and from the subject, a clinical laboratory and medical personnel, optimize palliative care that, based on at least the presence of variant alleles of two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1 , NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, IL12, IL13, IL18, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB 27 and loci specific for female and male gender directs a user to a specific palliative care clinical pathway for the subject or translate the data into recommendations for treatment options.

21. The kit of Claim 19, wherein the instructions generate a report for display to a clinician that can be printed or displayed on a computer monitor.

22. The kit of Claim 20 wherein the transmission of the data uses an electronic communication system that transmits the data to a distant computer system for processing.

23. A kit for generating a palliative care genomic profile for a subject, comprising:

a) reagents configured such that when exposed to a sample containing target nucleic acid from a palliative care subject the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, IL18, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and loci specific for female and male gender so as to generate a genomic profile for use in selecting a palliative care course of action for the subject; and

b) a computer program on a computer readable medium comprising instructions which direct a processor to analyze data derived from use of the reagents to indicate a palliative care treatment course of action.

24. A palliative care genomic profile kit having component parts configured such that when exposed to a sample containing target nucleic acid from a palliative care subject the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYPl A2, F2, F5, βarrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1 , NMDA, NKl, 5HT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, ILl 8, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB27 and Gender so as to generate a genomic profile for use in selecting a palliative care course of action for the subject and thereby providing a subject-specific clinical pathway for the subject comprising information to optimize palliative care that, based at least on the presence or absence of the variant alleles of two or more genes associated with two or more conditions selected from the group comprising OPRM-I, OPRDl, CYP2D6, CYP3A4, CYP1A2, F2, F5, barrestin2, stat2, COMT, MTHFR, A2a, melanocortin-1, NMDA, NKl, SHT3, ABCBl, ABRB2, CYP2C9, 5HT2a, ILIA, ILlB, IL2, IL4, IL6, IL8, ILlO, ILl 2, ILl 3, ILl 8, IL-IRa, PTGSl, PTGS2, STAT6, TGFβ, SCN9A, Navl.7, P2RX4, P2RX7, TNFa, TNFβ, TRPAl, TRPVl, FAAH, GCHI, NOSl, GIRKe, GABA-A, HLA-DRBl, UGTB 27 and loci specific for female and male gender measured by the kit, directs a user to a specific pathway of clinical intervention for the subject.

25. A kit for generating a palliative care genomic profile for a subject, comprising:

a) reagents configured such that when exposed to a sample containing target nucleic acid from a palliative care subject the reagents are sufficient to detect the presence or absence of variant alleles in two or more genes associated with two or more conditions selected from the group comprising somatic pain, visceral pain, neuropathic pain, nausea, over-sedation, dyspnea, cachexia, insomnia, fatigue and disorders of mood so as to generate a genomic profile for use in selecting a palliative care course of action for the subject; and

b) a computer program on a computer readable medium comprising instructions which direct a processor to analyze data derived from use of the reagents.